The reversible acetylation of the ε-amino groups of several lysine residues in the N-terminal histone tails mediates important conformational modifications in nucleosomes. These modifications influence the access of transcription factor to DNA and regulate gene expression (Davie, J. R. Curr. Opin. Genet. Dev. 1998, 8, 173-178). Two enzyme classes are involved in the process of acetylation and deacetylation of histones: histone acetyltransferases (HAT), which catalyse histone acetylation by acting as transcriptional co-activators, and histone deacetylases (HDAC).
After their recruitment to the promoter regions induced by transcription repressors and co-repressors such as Sin3, SMRT and N—CoR, histone deacetylases induce the formation of hypoacetylated histones and ultimately lead to transcriptional silencing (Wu, J. et al. Trends Biochem. Sci. 2000, 25, 619-623). The aberrant recruitment of histone deacetylases by oncogene proteins, or the disruption of the equilibrium between the activities of histone acetyltransferases and histone deacetylases are implicated in a series of pathologies, such as cancer, diseases of the central and peripheral nervous system, infections, immune diseases, cardiovascular diseases, muscular disorders, fibrosis or psoriasis.
The following (non exhaustive) selection of references demonstrate the involvement of HDACs in different diseases and the potential therapeutic benefit, which can be achieved by inhibiting them: Timmermann S. et al. Cell Mol Life Sci. 2001 58, 728-736; Huang, L. J. Cell. Physiol. 2006, 209, 611-616; Minucci, S. et al. Nature Reviews Cancer, 2006, 6, 38-51; Ouaissi, M. et al. J Biomed Biotechnol. 2006, 1-10; Sharma, P. et al. Schizophr. Res. 2006, 88, 227-231. Glozak M. A. et al. Oncogene. 2007, 26, 5420-5432; Elaut G. et al. Curr Pharm Des. 2007, 13, 2584-2620; Balakin K. V. et al. Anticancer Agents Med. Chem. 2007 7, 576-92; Lee H. B. et al. Kidney Int. Suppl. 2007, 106, S61-66; Morrison B. E. et al. Cell Mol Life Sci. 2007, 64, 2258-2269 Kazantsev A. G et al. Nat Rev Drug Discov. 2008, 7, 854-868.
In recent years there has been a considerable effort to develop inhibitors of histone deacetylases and several classes of compounds have been found to have potent and specific activities in preclinical studies. Their clinical benefits, however, are limited by toxicity problems, poor pharmacokinetic properties, poor potency and lack of selectivity (Elaut G. et al. Curr Pharm Des. 2007, 13, 2584-2620; Vigushin, D. et al. Anti-Cancer Drugs 2002, 13, 1-13).
PCT application WO 2004/113336 (Chroma Therapeutics) discloses carboline and betacarboline derivatives as HDAC inhibitors with the following general formula:
                wherein fused rings A1 and A2 are optional substituted, R1 represents a radical of formula -(Alk1)n—(X)m-(Alk2)p—Z, Z represents a radical of formula —C(═O)NH(OH) or N(OH)C(═O)Y.        
PCT application WO 2007/061880 (Merck) discloses spirocyclic compounds as HDAC inhibitors with the following general formula:
                wherein A, B and D are independently selected from CR12, NR1a, C(O) and O; E is selected from a bond, CR12, NR1a, C(O) and O; wherein at least one of A, B, D or E is CR12; G is CR12; R is selected from NH2 and OH; W and Z are aryl or heteroaryl.        
The present inventors have now found that certain substituted spirocyclic derivatives are highly potent inhibitors of the HDAC enzymes.